This invention relates to naphthalenylthiazole derivatives. More specifically, this application relates to 2-(1-naphthalenyl)thiazole derivatives, to processes for their preparation, to methods for using the derivatives, and to pharmaceutical preparations thereof. The derivatives have pharmaceutical properties which render them beneficial for the treatment of diabetes mellitus and associated conditions.
For many years diabetes mellitus has been treated with two established types of drugs, namely insulin and oral hypoglycemic agents. These drugs have benefited hundreds of thousands of diabetics by improving their well-being and prolonging their lives. However, the resulting longevity of diabetic patients has led to complications such as neuropathy, nephropathy, retinopathy, cataracts and atherosclerosis. These complications have been linked to the undesirable accumulation of sorbitol in diabetic tissue, which in turn result from the high levels of glucose characteristic of the diabetic patient.
In mammals, including humans, the key enzyme involved in the conversion of hexoses to polyols (e.g. the sorbitol pathway) is aldose reductase. J. H. Kinoshita and collaborators, see J. H. Kinoshita et al., Biochem. Biophys. Acta, 158, 472 (1968) and references cited therein, have demonstrated that aldose reductase plays a central role in the etiology of glactosemic cataracts by effecting the conversion of galactose to dulcitol (galactitol) and that an agent capable of inhibiting aldose reductase can prevent the detrimental accumulation of dulcitol in the lens. Furthermore, a relationship between elevated levels of glucose and an undesirable accumulation of sorbitol has been demonstrated in the lens, peripheral nervous cord and kidney of diabetic animals, see A. Pirie and R. van Heyningen, Exp. Eye Res., 3, 124 (1964); L. T. Chylack and J. H. Kinoshita, Invest. Ophthal., 8, 401 (1969) and J. D. Ward and R. W. R. Baker, Diabetol., 6, 531 (1970).
1,3-Dioxo-1H-benz[de]isoquinoline-2(3H)-acetic acid has been reported to be an effective inhibitor of aldose reductase, see D. Dvornik et al., Science, 182, 1146 (1973), and to be useful for the treatment of diabetic complications such as diabetic cataracts, neuropathy, nephropathy and retinopathy, see K. Sestanj, N. Simard-Duquesne and D. M. Dvornik, U.S. Pat. No. 3,821,383, June 28, 1974. Other compounds having a similar utility are the thioxo-1H-benz[de]isoquinoline-2(3H)-acetic acid derivatives of K. Sestanj, U.S. Pat. No. 4,254,108, Mar. 3, 1981 and 1H-benz[de]isoquinoline-2(3H)-acetic acid derivatives of K. Sestanj, U.S. Pat. No. 4,254,109, Mar. 3, 1981. Still other compounds having a similar utility are 2-thioxobenz[c,d]indole-1(2H)-acetic acid derivatives of K. Sestanj, U.S. patent application Ser. No. 284,049, filed July 17, 1981; N-naphthoylglycine derivatives of K. Sestanj et al., U.S. patent application Ser. No. 321,306, filed Nov. 13, 1981; N-(Naphthalenylthioxomethyl)amino acid derivatives of K. Sestanj et al., U.S. patent application Ser. No. 321,304, filed Nov. 13, 1981; N-[(2-naphthalenyl)thioxomethyl]glycine derivatives of K. Sestanj, U.S. patent application Ser. No. 321,303, filed Nov. 13, 1981; and N-[[6-(lower alkoxy)-5-(trifluoromethylthio)-1-naphthalenyl]thioxomethyl]-N-(lower alkyl)-glycines of F. Bellini et al., U.S. patent application Ser. No. 321,300, filed Nov. 13, 1981. (S)-6-Fluoro-2,3-dihydrospiro(4H-1-benzopyran-4,4'-imidazolidine)-2',5'-di one(sorbinil) is still another compound that has received attention because of its aldose reductase inhibiting properties (see M. J. Peterson et al., Metabolism 28 (Suppl. 1), 456 (1979). Accordingly, these compounds represent an important new approach for the treatment of diabetes mellitus.
The present application discloses novel naphthalenylthiazole derivatives, represented below by formula Ia and Ib, which are effective inhibitors of aldose reductase. These new derivatives are structurally quite different from the above noted aldose reductase inhibitors.
Previously reported naphthalenyltriazole derivatives differ from the present derivatives by having completely different substituents, by being at a different oxidation level in some instance, and by having completely different utilities. Typical examples of such naphthalenylthiazole derivatives are disclosed by T. S. Sulkowski and A. A. Mascitti, U.S. Pat. No. 3,539,585, Nov. 10, 1970; by J. J. Baldwin and G. Salvatore, European patent application No. 78100053.4, published Dec. 20, 1978 under No. 0 000 032; by L. G. S. Brooker, U.S. Pat. No. 2,441,558, May 18, 1948; and by J. D. Kendale et al., U.S. Pat. No. 2,474,426, June 28, 1949.